Mechanism of Action Classes of Antidepressant MedicationsClinical Effects and Side Effects
Things I always wanted to know aboutdepression, but I forgot I did not know
Response = 50% improvement ofsymptoms In the past decades the goal of treatment in depression was a response. Now the goal of treatment in depression is remission and recovery.
Remission vs. Recovery Remission: Patient is symptom free for 4-9 months. Recovery: Patient is symptom free for more than 12 months.
STAR*D Study In a large NIMH study called Sequenced Treatment Alternatives to Relieve Depression(STAR*D) the goal of treatment was remission. Only 1/3 of patients on Citalopram monotherapy remitted. 2/3 of patients failed to remit to Citalopram alone. If we are talking response instead of remission – 60- 70% of patients respond to SSRI monotherapy.
Relapse vs. RecurrenceWhat is a relapse? – Getting worse during the remission phaseWhat is a recurrence? – Getting worse during recovery phase
Remission rates in MDD Approximately one-third (33%) of depressed patients will remit during treatment with any SSRI monotherapy. Unfortunately, for those who fail to remit, the likelihood of remission with another antidepressant monotherapy goes down with each successive trial. Thus, after a year of treatment with four sequential antidepressants (from four different classes) taken for twelve weeks each, only two-thirds of patients will have achieved remission.
Common residual symptoms In patients who do not achieve remission(but achieve response), the most common residual symptoms are insomnia, fatigue, painful physical complaints, problems concentrating, and lack of interest. The least common residual symptoms are depressed mood, suicidal ideation, and psychomotor retardation.
Antidepressants - Actions
Antidepressants: complex drugs These are the known mechanisms through which antidepressants exert their actions: 1. Increase in monoamines 2. Increase in BDNF 3. Decrease in CRH 4. Increase of neurogenesis in hippocampus 5. Methylation of DNA(epigenetic factors) 6. Increase secretion of GDNF in glial cells
Monoamine Hypothesis Depression is due deficiency of monoamines: serotonin, dopamine or norepinephrine
All antidepressants (except MAO inhibitors) blockmonoamine transporter proteins Serotonin Transporter(SERT) Norepinephrine Transporter(NET) Dopamine Transporter(DAT)
In the Prefrontal Cortex Blocking NET Increases bothNorepinephrine and Dopamine In the human prefrontal cortex there are very few DAT. As a result dopamine diffuses outside of the synapse, accumulates in the prefrontal cortex and is eventually disposed of by NET. Thus drugs that block NET increase both Norepinephrine and Dopamine in the prefrontal cortex.
What is Neurotrophin Hypothesis? The reason why antidepressants work may not be the fact that they increase serotonin, dopamine or norepinephrine, but BDNF. BDNF is produced by the neurons and is encoded by a gene on chromosome 11.
BDNF Increases Dendritic Spines
Actions of BDNF-Sustains the viability of neurons (neuroprotection)-Increases dendritic arborization and the number of synapses.-BDNF gene is suppressed by stress (via cortisol).-Decreased BDNF levels lead to neuronal atrophy and neuronal death.- BDNF levels are low in depression, but increase with antidepressant treatment.- Exercise increases BDNF levels.
Psychopharmacologically speaking there areonly two classes of depressions
Serotonin Selective ReuptakeInhibitors (SSRIs) Six agents are in this class: Fluoxetine, Paroxetine, Sertaline, Fluvoxamine, Citalopram and Escitalopram. Fluvoxamine does not have an FDA indication for depression. It was approved for social phobia and OCD. In other countries it is being used for depression. Three agents come in CR form: Fluoxetine, Paroxetine and Fluvoxamine. All are generic except the CR preparations.
SSRIs overview Efficacy(FDA approved) for: MDD (all except Fluvoxamine) OCD( all except Citalopram and Escitalopram) Social Phobia(Sertaline, Fluvoxamine, and Paroxetine) PTSD(Sertaline and Paroxetine) Bulimia(Fluoxetine) GAD(Paroxetine and Escitalopram) PMDD(Fluoxetine, Paroxetine CR and Sertaline) Side Effects: GI, decreased libido, delayed ejaculation, headaches and Insomnia/Somnolence.
Serotonin NorepinephrineReuptake Inhibitors(SNRIs) Four agents: Venlafaxine, Desvenlafaxine, Duloxetine and Milnacipran Efficacy(FDA approved) for: -Venlafaxine(MDD, GAD, Social Phobia) -Desvenlafaxine(MDD) -Duloxetine(MDD, GAD, neuropathic pain, fibromyalgia) -Milnacipran(fibromyalgia) Off label uses: Venlafaxine (ADHD) Duloxetine (stress urinary incontinence) Desvenlafaxine(vasomotor symptoms associated with menopause)
Norepinephrine and DopamineReuptake Inhibitors(NDRIs) One drug: Bupropion FDA indication: MDD, smoking cessation and SAD. Off label use: depression in cardiac patients, adjunct to SSRIs (for depressed mood as well as to counteract sexual side effects), substance abuse problems, ADHD and weight loss. Mechanism of Action: mild dopamine reuptake inhibitor, norepinephrine reuptake inhibitor (via its metabolite hydroxybupropion). Adverse effects: 4/1000 risk for seizure disorder in immediate-release formulations (doses higher than 450 mg/day) and 1/1000 in sustained release formulations(identical to all other antidepressants).
Selective Norepinephrine ReuptakeInhibitors(NRIs) Two drugs: Atomoxetine and Reboxetine(not approved in US). Mechanism of Action: Block norepinephrine transportes. In the prefrontal cortex there are very few dopamine transporters. Norepinephrine transporters dispose of both norepinephrine and dopamine. For this reason when the norepinephrine transporters are blocked the levels of both NE and DA are increased. Atomoxetine (Strattera) has the FDA indication for ADHD, but off label it is used as antidepressant.
Alpha 2 Antagonists as Serotonin andNorepinephrine Disinhibitors(SNDIs) One drug: Mirtazapine FDA indication: MDD Off label uses: panic d/o, GAD, negative symptoms of schizophrenia, anti-nausea medication in chemotherapy patients(Kim 2008)and post operative nausea(Chen 2008). In STAR*D trial the combination of Mirtazapine(average dose 36 mg/day) with Venlafaxine (average dose 210 mg/day) resulted in remission of 13% of patients who failed three consecutive antidepressant trials(McGrath 2006). Mechanism of action: Blocks alpha 2 adrenergic receptors presynaptically(autoreceptors) on noradrenergic and serotonergic neurons, leading to disinhibition of serotonin and norepinephrine. In addition, mirtazapine blocks 5HT2A, 5HT2C and 5HT3 postsynaptically.
Serotonin Antagonist/ReuptakeInhibitors(SARIs) Two agents: Trazodone, Nefazodone Both have FDA indication for MDD. Off label use: anxiety (Trazodone), PTSD (Nefazodone one of the most prescribed drugs for PTSD). Depression with co-morbid substance abuse (Nefazodone). Mechanism of Action: presynaptically blocks the serotonin transporters and 5HT1A postsynaptically blocks 5HT2A, 5HT2C Adverse effects: liver damage (risk 1/250,000 per patient/year) = If a quarter of a million patients were taking Nefazodone for a year , one patient would be expected to develop liver damage.
Serotonin Partial Agonist ReuptakeInhibitor (SPARI) Vilazodone (Viibryd) approved in January 2011. FDA approved for Major Depressive Disorder Off label used for Anxiety Mechanism of action:-blocks serotonin reuptake pumps-partial agonist at presynaptic somatodendritic 5HT 1ADosage:40 mg once daily with food (taken on empty stomach 50%reduced absorbtionSide effects: nausea, diarrhea, insomnia, rare hyponatremia
Tricyclic Antidepressants(TCA) Efficacy: Second or third line agents for MDD, Panic d/o, OCD (FDA approved Clomipramine), Pain Syndromes, Migraine prophylaxis, Enuresis (FDA approved Imipramine). Side Effects: dry mouth, urinary retention, constipation, blurred vision, confusion, weight gain, sedation, sexual dysfunction, orthostasis, tachycardia and cardiac conduction abnormalities. Drug interactions: TCA increase warfarin levels, cimetidine increases TCA levels, clonidine – hypertensive crises(avoid), oral contraceptives – increase TCA levels, SSRIs increase TCA levels, quinidine with TCA- increase in arrhythmias(avoid), L- dopa decreases TCA levels, sympathomimetics with TCAs – risk for arrhythmia, HTN, tachycardia.
MAO Inhibitors (MAOI) Efficacy: Third line agents for MDD, second line for Parkinson’s disease(Selegiline). FDA indications: treatment resistant depression. Selegiline(Emsam) was approved by the FDA in 2006 in the transdermal form for depression (oral Selegiline is not approved for depression). The Selegiline dilemma: Selegiline is a MAO-B inhibitor and in the doses used for Parkinson’s disease (5-10 mg a day) has a low risk for hypertensive crises. Unfortunately for the treatment of depression higher doses (40-60 mg a day) are needed. At these high doses the drug affects both MAO-A and MAO-B and the risk for hypertensive crises is high. The transdermal Selegiline(Emsam) bypasses the gut and the liver and thus allows for use of higher doses with lower risk for hypertensive crises(below 60 mg a day).
Drug Interactions and AdverseEffects Risk of serious drug interactions is limited with SSRIs, except in two circumstances: -Fatalities have been reported from serotonin syndrome when used in close proximity with MAOI, even if the drugs were not used concurrently. -Inhibition of 2D6 enzyme by the SSRIs. Many drugs are metabolized by this enzyme, including TCA, type 1C antiarrhythmic agents, some beta blockers, benztropine and many antipsychotics. SSRIs inhibit 2D6, leading to increased plasma levels of other agents (8 fold increase in TCA plasma levels have been reported when used together).
Antidepressants During Pregnancy(damned if you do, damned if you don’t)
T3/T4 augmentation of antidepressants(in thyroid deficiency)
Lithium increases the efficacy ofantidepressants(lithium augmentation)
L-5-methyl-tetrahydrofolate(MTHF) MTHF(unlike folate) crosses the BBB and activates the enzymes that lead to the formation of NE, DA and 5HT. These are the rate limiting enzymes such as triptophan hydroxilase(5HT)and thyrosine hydroxilase(DA and NE).
Vagus Nerve Stimulation The vagus nerve connects with the neurotransmitter centers in the brainstem(locus coeruleus and raphe nuclei). A pacemaker -like device is implanted in the chest wall with an implanted lead wrapped around the vagus nerve in the neck area. The device delivers pulses to the vagus nerve, which in turn boost monoamine neurotransmission.
Transcranial Magnetic Stimulation(TMS) Rapidly alternating current passes through a small coil placed over the scalp. This generates a magnetic field that induces an electrical current in the DLPFC. The affected neurons then signal other areas of the brain VMPFC and amygdala, giving a triaminergic boost.
Deep Brain Stimulation Effective for the treatment of motor complications in Parkinson’s disease and is now used in some centers for treatment resistant depression. Consists of a battery -powered pulse generator implanted in the chest wall like a pacemaker. One or two electrodes are implanted into the subgenual area of ACC .
Glucocorticoid Receptor Antagonists Several reports suggested that Mifeprestone (RU-486) was beneficial in MDD with psychotic features (DeBattista et al. 2006)
Beta 3 Agonists
Ketamine and other Glutamate Blockers Ketamine 0.5 mg/Kg intravenously administered to patients with major depression was found to exert a rapid (2 hours) postinfusion antidepressant effect lasting about a week(Zarate et al. 2006).
References: Stahl’s Essential Psychopharmacology, Third Edition, 2010 Textbook of Psychopharmacology, Fourt Edition, Schatzberg, Nemeroff, 2010 Brain Protection in Schizophrenia, Mood and Cognitive Disorders, Ritsner et al, 2010